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Palliation of Opioid-Induced Constipation

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Palliation of Opioid-Induced Constipation 7/6/2016 DEFINITIONS • Opioid-Induced Constipation (OIC) vs 2016 ANNUAL MEETING Reflux Bloating • Opioid-Induced Bowel Dysfunction (OIBD) Abdominal cramping motility Hard/dry stools PALLIATION OF OPIOID-INDUCED coordination of sphincter function Incomplete evacuation CONSTIPATION: WHAT’S NEW coordination of secretion Shelley S. Spradley, PharmD, BCPS Clinical Pharmacy Specialist: Pain Management, Palliative Care Poulsen et al. 2015. 2016 ANNUAL MEETING OBJECTIVES OIBD/OIC PREVALENCE & IMPACT • Review prevalence and impact of opioid-induced ** Lack of uniform definition, interpret with caution ** constipation (OIC) • OIC probably most well characterized adverse event in opioid-treated patients • 15-81% in patients without cancer • Discuss the available treatment options for OIC with an • Multinational, internet-based survey of 322 chronic opioid users: 81% despite use emphasis on pathophysiology of laxatives • Larger, population-based survey of 2055 pts on opioids + laxatives for chronic non- • Devise a therapeutic plan to incorporate new cancer pain: 57% prevalence of constipation pharmacologic agents for refractory constipation 1. Moore RA et al. 2005. 2. Bell TJ et al. 2009. 2016 ANNUAL MEETING 2016 ANNUAL MEETING CASE TOWARDS A CONSENSUS DEFINITION OF OIC • 46yo WF with PMH significant for stage V breast cancer, left sided malignant pleural effusion s/p PleurX catheter A change when initiating opioid therapy from baseline presenting with shortness of breath. Medicine team bowel habits that is characterized by any of the following: consult for pharmacy pain evaluation due to high dose opioid analgesics and non-formulary Relistor • Reduced bowel movement frequency • Morphine SA 300mg po q8h • Development or worsening of straining to pass bowel • Hydromorphone 16mg po q3h prn movements • Metoclopramide 10mg po tid • Docusate 100mg po bid • Sense of incomplete rectal evacuation • Senna 17.2mg po bid • Harder stool consistency • Polyethylene glycol 17grams po bid • Methylnaltrexone(Relistor) 12mg/0.6ml SubQ q48h Camilleri M et al. 2014. 2016 ANNUAL MEETING 2016 ANNUAL MEETING 1 7/6/2016 ASSESSMENT TOOLS TREATMENT • Currently, laxatives are primary • Bowel Function Index (BFI) treatment of OIBD • Newer agents • Lubipristone (Amitiza) • Patient Assessment of Constipation-Symptoms • Previously approved peripherally acting • Naloxegel (Movantik) • Bristol Stool Chart mu opioid receptor antagonists (PAMORAs) • TD-1211 (Axelopran) • Electronic Bowel Function Diary • Methylnaltrexone (Relistor) • Naloxone Sustained Release • Alvimopan (Entereg) 1. Morlion B et al. 2015. 2. Frank L et al. 1999. 3. Lewis SJ et al. 1997. 1. Coyne KS et al. 2014 4. Camilleri M. 2011. 2. Siemens W et al. 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING PATHOPHYSIOLOGY LET’S NOT FORGET…. • 3 types of opioid receptors involved in controlling normal GI function • Mu, Delta, Kappa • Many patients have inadequate traditional bowel regimens • Docusate, senna/bisacodyl, lactulose, sorbitol, • Endogenous and exogenous opioids activate Mu receptors polyethylene glycol, steroids(obstruction), prune • Ultimately inhibit conversion of ATP to cAMP, reduce cellular functions juice, various enemas and suppositories, manual dis-impaction, digital rectal stimulation... • Opioids also directly activate K+ channels and inhibit Ca2+ • Failure of “prn” bowel regimens does not • Net result = reduced release of neurotransmitters, necessitate escalation to new, costly agents decreased neuronal activity 1. Holzer P. 2004. 2. Holzer P. 2009. 2016 ANNUAL MEETING 2016 ANNUAL MEETING PATHOPHYSIOLOGY DRIVING TREATMENT OLDER AGENTS 1. Dryer, harder stool Methylnaltrexone (Relistor) Almivopan (Entereg) MOA PAMORA PAMORA 2. Feeling of incomplete evacuation FDA • OIC including in advanced illness • Post-operative ileus following certain Indications patients receiving palliative care surgeries • FDA warning for bowel perforation in Warnings • BBW, active REMS program advanced cancer patients 3. Reduced propulsive peristalsis • 12mg SubQ every other day prn • 12mg PO 30min-5hr prior to sx Dosing • Max 1 dose/24hr • 12mg PO bid starting day after sx for ≤ 7d • Weight and renal dose adjustments • Renal and hepatic dose adjustments 1. Holzer P. 2004 1. Thomas J et al. 2008 2. Holzer P. 2009 2. Jansen JP et al. 2011. 3. Holder RM et al. 2016. 3. Merck & Co Inc. 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING 2 7/6/2016 NEWER AGENTS ON THE HORIZON Sustained Release Pearls from Clinical Studies Lubiprostone (Amitiza) Pearls from Clinical Studies Naloxone (NSR) MOA Chloride channel activator • Significant increase in spontaneous bowel movements Modified release reduces • 40 patients randomized in blocks to receive 2.5mg, MOA systemic concentrations, acts • CIC (2006), IBS (2008) (SBMs)/week compared to placebo 5mg, 10mg or 20mg FDA Indications like a PAMORA • 6 week study, doses inc’d to BID at week 4 • OIC (2013) • Median time to 1st BM 28.5h (not different than placebo) • Not approved as single agent • At week 3, mean change in SBMs/week was • Long-term efficacy over 9 months found inc’d number of FDA • Oxycodone ER/naloxone statistically significant compared to placebo for only SBMs/week from 1.4 at baseline to 4.9 Indications • 24mcg PO BID with food fixed combo approved 20mg and water • Not superior to placebo in reliance on rescue therapy w/ Dosing • At week 6, only 10mg BID dose achieved statistical • Dose adjusted for laxative • 2.5mg/day - 40mg/day orally significance compared to placebo hepatic impairment has been studied • Improvements in OIBD symptoms noted (straining, Dosing • OxyER/naloxone not being • Opioid withdrawal: no statistically significant change severity of constipation, bloating) manufactured from baseline or compared to placebo 1. Cryer B et al 2014. 1. Holder RM et al. 2016. 2. Jamal MM et al. 2015. 2. Sanders M et al. 2015. 2016 ANNUAL MEETING 2016 ANNUAL MEETING NEWER AGENTS CASE REVISITED Naloxegol (Movantik) Pearls from Clinical Studies • 46yo WF with PMH significant for stage V breast cancer MOA Pegylated naloxone derivative • KODIAC 04, KODIAC 05 • Last BM 4 days prior FDA Indications • OIC in CNCP (2014) • Statistically significant improvements in straining, stool consistency, and complete spontaneous • Normal: BM every other day, bristol stool type 2, endorses moderate • 25mg po daily, empty stomach bowel movement (SBM) straining with each BM, frequent feeling of incomplete evacuation • 12.5mg achieved significantly greater • Reduce to 12.5mg for: response than placebo in KODIAC 04 only • Scenario 1 • Intolerance • 25mg dose reach statistical significance in • Continue current bowel regimen, including methylnaltrexone 12mg SubQ q48hr Dosing both studies • CrCl less than 60ml/min • Add docusate mini enema (Enemeez), 2 enema NOW PR then q48hr • Co-administered with • 25mg dose resulted in shorter median time moderate CYP3A4 to first SBM • Scenario 2 inhibitors • No significant difference in bisacodyl use • Discontinue methylnaltrexone, continue docusate, senna, polyethylene glycol between treatment arms • Add enema or suppository “NOW” dose 1. Chey WD et al. 2014. 2. Webster L et al. 2014. • Add lubipristone 24mcg PO BID with food, water 3. Holder RM et al. 2016. 2016 ANNUAL MEETING 2016 ANNUAL MEETING ON THE HORIZON CLINICAL PEARLS TD-1211 (Axelopran) Pearls from Clinical Studies • Safe to assume opiates/opioids constipate everyone MOA PAMORA • Efficacy evaluated in three phase 2 studies • Bowel regularity assessment should include discussion FDA beyond frequency • Not yet approved Indications • Definitions of OIC, spontaneous bowel movement (SBM) or complete SBM were not provided • Pathophysiology of OIC/OIBD often results in dry/hard stools, incomplete evacuation, and reduced propulsive • No formal • Doses of 5 and 10mg produced greatest SBMs/week peristalsis recommendation, has • Median time to first SBM 8.6hrs (5mg) and 3.6hrs Dosing been studied most (10mg) compared to 28.7hr(placebo) • Newer agents do not replace standard of care recently at 5mg, 10mg, • Many agents were only studied against placebo 15mg orally • Studies reported no clinically significant changes in lab tests, ECG, or vital signs (but did not report the data) • Rescue laxatives were required in most clinical studies 1. Holder RM et al. 2016. 2. Axelopran (TD-1211) briefing document: 2014 2016 ANNUAL MEETING 2016 ANNUAL MEETING 3 7/6/2016 REFERENCES • Poulsen JL, Brock C, Olesen AE et al. Evolving paradigms in treatment of opioid-induced bowel dysfunction. Ther Adv Gastroenterol 2015;8(6):360-72. • Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: a systematic review of randomised trials of oral opioids. Arthritis Res Ther 2005;7:R1046-51 • Bell TJ, Panchal SJ, Miaskowski C et al. The prevalence, severity and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 2009;10:35-42. • Camilleri M, Drossman DA, Becker G et al. Emerging treatments in neurogastroenterology: a multidisciplinary working group concensus statement on opioid- induced constipation. Neurogastroenterol Motil 2014; 26(10):1386-95 • Morlion B, Clemens KE, Dunlop W. QuaIity of life and healthcare resource in patients receiving opioids for chronic pain: a review of the place of oxycodone/naloxone. Clin Drug Investig 2015;35(1):1-11. • Frank L, Kleinman L, Farup C et al. Psychometric validation of a constipation assessment questionnaire. Scan J Gastroenterol 1999;34(9):870-77. • Lewis SJ, Heaton KW. Stool form scale as a useful guide to
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